Derivatives of 3-(5-nitrofur-2-yl)-5-aminoisoxazoles

ABSTRACT

3-(5-NITROFUR-2-YL)-5-AMINOISOXAZOLES HAVING A ITRILE, ESTER, AMIDE OR UREA FUNCTION IN THE 4-POSITION ARE ANTIBACTERIAL AGENTS. THEY ARE PREPARED THROUGH CONDENSATION OF 5-NITRO-2-FUROHYDROXAMOYL HALIDE WITH A CYANOMETHYLNITRILE, A CYANOMETHYLESTER, CYANOMETHYLAMIDE OR A CYANOMETHYLUREA UNDER BASIC CONDITIONS.

United States Patent ABSTRACT OF THE DISCLOSURE3-(S-nitrofur-Z-yl)5-aminoisoxazoles having a nitrile, ester, amide orurea function in the 4-position are anti bacterial agents. They areprepared through condensation of S-nitro-2-furohydroxamoyl halide with acyanomethylnitrile, a cyanomethylester, cyanomethylamide or acyanomethylurea under basic conditions.

DETAILED DESCRIPTION The present invention relates to substitutedheterocyclic compounds, and in particular to nitrofuryl derivatives ofisoxazoles and to processes for the production of these compounds.

According to the present invention, there is provided a5-nitro-2-furyl-isoxazole having the Formula I wherein R is a CN,--CO.OR or grouping, the group R being a straightor branched-chain alkylgroup containing from 1 to 6 carbon atoms, the alkyl group beingunsubstituted or hydroxyl-, alkoxyor halogen-substituted, a straightorbranched-chain alkenyl group containing 3 or 4 carbon atoms; or acycloalkyl group; the group R being hydrogen and the group R beinghydrogen, a straightor branched-chain alkyl group containing from 1 to12 carbon atoms, the alkyl group being unsubstituted or hydroxyl,alkoxyor halogen-substituted, a straightor branched-chain alkenyl groupcontaining 3 or 4 carbon atoms, cycloalkyl, carbalkoxy the alkyl portionof which is a straightor branched-chain alkyl group containing from 1 to5 carbon atoms, or carbamoyl; or R and R together form a straight orbranched alkylene chain containing from 2 to 7 carbon atoms,uninterrupted or interrupted by an oxygen, nitrogen or sulphur atom.

If R or the group R is alkyl, each of these groups may be, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl,tertiary butyl, n-amyl, isoamyl or n-hexyl. Alkyl groups having from 1to 4 carbon atoms are particularly preferred. If either R or R is analkyl group subsittuted by a halogen substituent, the halogen may befluorine or iodine but is preferably chlorine or bromine. If either R orR is an alkyl group which is hydroxyl-, alkoxyor halogen-substituted,preferably the alkyl group contains 1 or 2 halogen, alkoxy or hydroxylsubstituents. If either R or R is an alkenyl group, this may be, forexample, allyl, Z-methallyl, 2-butenyl (crotyl) or 3-butenyl. If eitherR or R is a cyclo alkyl 3,562,267 Patented Feb. 9, 1971 group, this maybe, for example, cyclohexyl. If the group R is a carbalkoxy group, thealkyl portion of the carbalkoxy group may be, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl or n-amyl.

If the groups R and R together form' an alkylene chain uninterrupted byan oxygen, nitrogen or sulphur atom, this chain may be, for example,ethylene, trimethylene, propylene, tetramethylene, methyl-substitutedtrimethylene, dimethyl-substituted ethylene, pentamethylene,hexamethylene, heptamethylene or dimethyl-substituted pentamethylene. Ifthe alkylene chain is interrupted by an oxygen atom, the grouping R thusformed may be, for example, morpholinocarbonyl; if the alkylene chainformed by R and R together is interrupted by a nitrogen atom (preferablyin the form of a grouping NQ- where Q is hydrogen or an alkyl grouphaving from 1 to 3 carbon atoms) or by a sulphur atom, the grouping Rthus formed may be, for example, a l-piperazinylcarbonylor athiomorpholino-carbonyl grouping, respectively.

Particularly preferred compounds of the invention have the Formula Iwherein R is a CN group or is a 7 Formula II OzN 04: 0 a

wherein X represents a halogen atom, with a reactive methylene compoundhaving the Formula 111 (III) wherein Y represents hydrogen or an alkalimetal and R has the previous significance. The reaction between the5nitro-2-furohydroxamoyl halide and the reactive methylene compound ofFormula III is conveniently carried out in the presence of a basiccondensation promotor, preferably sodium methoxide.

The reactive methylene compound of Formula III used in the reaction maybe the compound having the formula NCCH -R or a corresponding reactivealkali metal derivative, preferably the sodium derivative, having theformula NCCH(M)R wherein M is an alkali metal.

The 5nitro-2-furohydroxa-moyl halide of Formula II is preferably thechloride or bromide. The halides may be prepared by conventionalmethods: the chloride may be obtained, for instance, by the methoddescribed by Doyle, Hanson, Long and Nayler in the Journal of theChemical Society (1963) at page 5845 or by that described in HelveticaChimica Acta (1963) volume 46 at page 1067. The halide used as startingmaterial in the process of the invention may be a purified product or itmay be the crude product so prepared, if desired, after partialpurification.

The reactive methylene compound of Formula III may be, for instance,malononitrile, cyanoacetamide or an N- substituted cyanoacetamide; or anester of cyanoacetic acid. Examples of preferred reactive methylenecompounds are given in the following table in which the appropriate Rsubstituents of Formula III are stated.

Compound: R

Malononitrile N Cyanoacetamide CONH Cyanoacetylpyrrolidine CO.NCH CH CHCH 18 (N cyanoacetylamino)- ethanol CO.NH.CH CH OH Methyl cyanoacetateCOOCH Ethyl cyanoacetate COOC H Isopropyl cyanoacetate COOi-C H Allylcyanoacetate COOC H N-allyl cyanoacetamide CONHC H Cyanoacetyl ureaCONHCONH p Chloroethyl c y a n oacetate COOCH CH CI The presentinvention also provides a second process of producing a5-nitro-2-furyl-isoxazole of Formula I wherein R represents the CNgrouping, which comprises dehydrating the corresponding 5 nitro2-furylisoxazole of Formula I wherein R represents the -CO.NH grouping.

The dehydration may be carried out, for example, by heating at anelevated temperature, preferably at a temperature in the range of from50 C. to the boiling point of the reaction mixture under reflux. Theprocess is preferably carried out in the presence of a conventionalagent for dehydrating carbamoyl compounds to the corresponding nitriles,for instance phosphorus oxychloride.

Although the compounds of the present invention have been ascribed theFormula I above, they may also be represented by either or both of thefollowing tautomeric Formulae IA and IB, and any specific compound ofthe invention may occur in any of these tautomeric forms or as a mixtureof two or all thereof.

N\ C=NH EN C=NH In this specification, however, the compounds areregarded for purposes of clarity as having the Formula I and are thusdescribed and exemplified as being nitrofuryl-isoxazole derivatives.

The compounds of the invention have useful pharmacological and, inparticular, antimicrobial properties, being valuable antibacterial,antifungal, antiviral, anthelmintic, coccidiostatic or growth-promotingagents for external or internal pharmaceutical uses.

The novel compounds according to the invention have been found toexhibit outstanding antimicrobial activities, in particularantibacterial activity. In living organisms they are active, forexample, against general Staphylococcal infections and infections due toSalmonella and Escherichia coli species.

The following compounds have been demonstrated to be effective asbacteriostatic agents against Staphylococcus aureus, Escherichia coli,and Mycobacterz'um tuberculosis (isonicotinoyl hydrazide resistant andstreptomycin resistant strains):

The compounds are particularly valuable in the treatment of infectionsof the intestinal or urinary tract. The compounds may also be used toprotect an organic material susceptible to bacterial, fungal or othermicrobial 4 deterioration by contacting with, impregnation in orotherwise treating the material with the compounds.

Accordingly, the invention also provides a composition comprising anantimicrobially effective proportion of a S- nitro-Z-furyl-isoxazole ofFormula I and a pharmacologically acceptable solid carrier or liquiddiluent.

The pharmaceutical compositions according to the invention contain atleast one compound of general Formula I as active substance togetherwith a conventional pharmaceutical carrier. The type of carrier actuallyused depends to a great extent on the intended application: for externaluse, for example in disinfecting healthy skin, disinfecting woundsand-in treating dermatoses and affections of the mucous membranes causedby bacteria ointments, powders and tinctures are used in particular. Theointment bases may be anhydrous, for instance they can consist ofmixtures of wool fat and soft paraffin, or they can consist of aqueousemulsion in which the active substance is suspended. Suitable carriersfor powders are, for instance, rice starch and other starches; the bulkweight of the carriers may be made lighter, if desired, for example byadding highly dispersed silicic acid, or may be made heavier by addingtalcum. The tinctures may contain at least one active ingredient of theFormula I in aqueous ethanol, in particular 45% to 75% ethanol, to which10% to 20% of glycerol may be added, if desired. Solutions prepared frompolyethylene glycol and other conventional solubility promoters, andalso optionally, from emulsifying agents, may be used with particularadvantage in disinfecting healthy skin. The content of active ingredientin pharmaceutical compositions for external application is preferably inthe range of from 0.1% to 5%.

Gargles or concentrates for their preparation, and tablets for slowdissolution in the mouth, are suitable for the disinfection of the mouthand throat. The former are preferably prepared from alcoholic solutionscontaining 1% to 5% of active substance to which glycerol or flavouringsmay be added. Lozenges, that is solid dosage units, preferably have arelatively high content of sugar or similar substances and a relativelylow content of active substance, for instance 0.2% to 20% by Weight, aswell as the usual conventional additives such as binding agents andfiavourings.

Solid dosage units, in particular tablets, dragees (sugar coatedtablets) and capsules, are convenient for use in intestinal disinfectionand for the oral treatment of urinary tract infections. These unitspreferably contain from 10% to of the compounds of the general Formula Ito enable the administration of daily doses of from 0.1 to 2.5 grams toadults, or of suitable reduced doses to children, to be made. Tabletsand drage cores are produced by combining the compounds of the generalFormula I with solid, pulverulent carriers such as lactose, saccharose,sorbitol, maize starch, potato starch or amylopectin, cellulosederivatives or gelatines, preferably with the addition of lubricantssuch as magnesium or calcium stearate or polyethylene glycols ofsuitable molecular weight. Drage cores may then be coated, for examplewith concentrated sugar solutions which can also contain gum arabic,talcum and/or titanium dioxide, or they may be coated with a lacquerdissolved in volative organic solvents or mixture of solvents. Dyestuffscan be added to these coatings, for instance to differentiate betweenvarying dosages. Soft gelatine capsules and other closed capsulesconsist, for example, of a mixture of gelatines and glycerol and maycontain, for example, mixtures of the compound of Formula I withpolyethylene glycol. Hard gelatine capsules contain, for example,granulates of an active substance with solid pulverulent carriers, forinstance lactose, saccharose, sorbitol, mannitol, starches (such aspotato starch, maize starch or amylopectin), cellulose derivatives ofgelatines, and magnesium stearate or stearic acid.

In all forms for administration, compounds of the general Formula I canbe present as sole active ingredients or they can also be combined withother known pharmacologically active, and especially antibacterial and/or antimycotically or other antimicrobially active substances, forexample to broaden the range of application. They can be combined forexample, with 5,7-dichloro-2- methyl-S-quinolinol or other derivativesof 8-quinolinol, with sulfamerazine or sulfafurazole or otherderivatives of. sulfanilamide, with chloramphenicol or tetracycline orother antibiotics, with 3,4,5-tribromosalicylanilide or otherhalogenated salicylanilides, with halogenated carbanilides, withhalogenated benzoxazoles or benzoxazolones, withpolychlorohydroxy-diphenylmethanes, with halogen-dihydroxy-diphenylsulphides, with 4,4-dichloro- 2-hydroxy-diphenylether or2',4,4'-trichloro-2-hydroxydiphenylether or otherpolyhalogen-hydroxydiphenylethers, or with bactericidal quaternarycompounds or with certain dithiocarbamic acid derivatives such astetramethylthiuram disulphide. Also, carriers which themselves havefavourable pharmacological properties may be used, for instance sulphuras powder base or zinc stearate as a component of ointment bases.

The invention also provides a method of protecting an organic materialsusceptible to bacterial, fungal or other microbial attack whichcomprises treating the material with a -nitro-2-furyl-isoxazole ofFormula I. The organic material may be, for instance, a natural orsynthetic polymeric material, a proteinaceous or carbohydrate substance,or a natural or synthetic fibre or textile material formed therefrom.

The following examples further illustrate the present invention. Thetemperatures are given in degrees centigrade.

EXAMPLE 1 A solution of 1.15 g. of metallic sodium dissolved in 20 ml.of anhydrous methanol was added slowly to a mixture of 9.5 g. of5-nitro-2-furohydroxamoylchloride and 3.3 g. of malononitrile dissolvedin 80 ml. of anhydrous methanol at 20 to 25.

After allowing to stand, the crystalline precipitate was collected,washed with water and recrystallised from a mixture of water anddimethylformamide. The product was 3-( 5 '-nitrofuryl-2)-4-cyano-S-amino-isoxazole, having melting point 263 with decomposition.

EXAMPLE 2 The procedure described in Example 1 was carried out using themolecular equivalent of cyanacetamide as starting material instead ofthe malononitrile, the reaction conditions being otherwise essentiallythe same.

The product was 3-(5nitrofuryl-2')-4-carbamoyl-5- amino-isoxazole,having melting point 212 with decomposition.

EXAMPLE 3 A solution of 1.15 g. of metallic sodium dissolved in 20 ml.of anhydrous methanol was added slowly to a mixture of 9.5 g. of5-nitro-2-furohydroxamoylchloride and 7.6 g. of l-cyanoacetylpyrrolidinedissolved in 120 ml. of anhydrous methanol at 20 to 25.

After allowing to stand, the crystalline precipitate was collected,washed with water and recrystallised from a mixture of water anddimethylformamide.

The product was3-(5-nitrofuryl-2)-4-pyrrolidinocarbonyl-S-amino-isoxazole, havingmelting point 186.

The 1-cyanoacetylpyrrolidine used as reactant in the process of Example3 was prepared by the following method:

A mixture of 113 g. of ethyl cyanoacetate and 71 g. of pyrrolidine washeated at 110 in a distillation apparatus until the distillation ofliberated alcohol ceased. After cooling, the residue was recrystallisedfrom ethyl acetate. The product was 1-cyanoacetylpyrrolidine, havingmelting point 70.

6 EXAMPLE 4 The procedure described in Example 3 was carried out usingthe molecular equivalent of l-cyanoacetylpiperidine as starting materialinstead of the l-cyanoacetylpyrrolidine, the reaction conditions beingotherwise essentially the same.

The product was3-(5'-nitrofuryl-2')-4-piperidinocarbonyl-5-amino-isoxazole, havingmelting point 188 with decomposition.

EXAMPLE 5 The procedure described in Example 3 was carried out using themolecular equivalent of ethyl cyanoacetylcarbamate as starting materialinstead of 1-cyanoacetylpyrrolidine, the reaction conditions beingotherwise essentially the same.

The product was3-(5-nitrofuryl-2)-4-ethoxycarbonylcarbamoyl-S-amino-isoxazole, havingmelting point 218 with decomposition.

EXAMPLE 6 A solution of 2.3 g. of metallic sodium dissolved in 40 ml. ofanhydrous ethanol was added slowly to a mixture of 19.1 g. of 5nitro-2-furohydr0xamoyl chloride and 11.3 g. of ethyl cyanoacetatedissolved in ml. of anhydrous ethanol at 20 to 25.

After allowing to stand, the crystalline precipitate was collected,washed with water and recrystallised from a mixture of water anddimethylformamide.

The product was 3-(5-nitrofuryl-2)-4-ethoxycarbonyl- S-amino-isoxazole,having melting point 200.

EXAMPLE 7 The procedure described in Example 3 was carried out using themolecular equivalent of N-cyanoacetylmorpho line as starting materialinstead of the 1-cyanoacetylpyrrolidine, the reaction conditions beingotherwise essentially the same.

The product was 3-(5'-nitrofuryl-2')-4-morpholinocarbonyl 5amino-isoxazole, having melting point 245 with decomposition.

EXAMPLE 8 The procedure described in Example 3 was carried out using themolecular equivalent of cyanoacetyl urea as starting material instead of1-cyanoacetylpyrrolidine, the reaction conditions being otherwiseessentially the same.

The product was 3-(5'-nitrofuryl-2')-4-ureidocarbonyl-S-amino-isoxazolehaving melting point 208 with decomposition.

EXAMPLE 9 The procedure described in Example 3 was carried out using themolecular equivalent of fl-(N-cyanoacetylamino)-ethanol as startingmaterial instead of l-cyanoacetylpyrrolidine, the reaction conditionsbeing otherwise essentially the same.

The product was3-(5'-nitrofuryl-2')-4-(fl-hydroxyethyl-carbamoyl)-5-amino-isoxazole,having melting point 209 with decomposititon.

EXAMPLE 10 EXAMPLE 11 A solution of 2.3 g. of metallic sodium dissolvedin 40 ml. of anhydrous methanol was added slowly to a mixture of 19.1 g.of S-nitro-Z-furohydroxamoyl chloride and 9.9 g. of methyl cyanoacetatedissolved in 120 m1. of anhydrous methanol at to After allowing tostand, the crystalline precipitate was collected, washed with water andrecrystallised from a mixture of water and dimethylformamide.

The product was 3-(5-nitrofuryl-2)-4-methoxycarbonyl-S-amino-isoxazolehaving melting point 240 with decomposition.

EXAMPLE 12 The procedure described in Example 11 was carried out usingthe molecular equivalent of isopropylcyanoacetate as starting materialinstead of the methyl cyanoacetate, the reaction condititons beingotherwise essentially the same.

The product was3-(5'-nitrofuryl-2)-4-isopropoxycarbonyl-S-amino-isoxazole havingmelting point 174.

EXAMPLE 13 The procedure described in Example 11 was carried out usingthe molecular equivalent of allyl cyanoacetate as starting materialinstead of methyl cyanoacetate, the reaction conditions being otherwiseessentially the same.

The product was 3-(5-nitrofuryl-2')-4-allyloxycarbonyl-5-amino-isoxazolehaving melting point 124.

EXAMPLE 14 The procedure described in Example 11 was carried out usingthe molecular equivalent of cyclohexyl cyanoacetate as starting materialinstead of the methyl cyanoacetate, the reaction conditions beingotherwise essentially the same.

The product was3-(S-nitrofuryl-2)-4-cyclohexyloxycarbonyl-5-amino-isoxazole havingmelting point 170.

Similarly, by using n-hexyl cyanoacetate instead of the methylcyanoacetate, the product obtained is 3-(5'-nitrofuryl-Z -4-(n-hexyloxycarbonyl -5 -amino-isoxazole, having melting point 185 to187.

EXAMPLE 15 The procedure described in Example 3 was carried out usingthe molecular equivalent of N-methylc-yanoacetamide as starting materialinstead of the l-cyanoacetylpyrrolidine, the reaction conditions beingotherwise essentially the same.

The product was 3-(5'-nitrofuryl-2)-4-methyl-carbamoyl-5-amino-isoxazolehaving melting point 238 with decomposition.

EXAMPLE 16 The procedure described in Example 3 was carried out usingthe molecular equivalent of N-ethylcyanoaceta mide as starting materialinstead of the l-cyanoacetylpyrrolidine, the reaction conditions beingotherwise essentially the same.

The product was 3-(5-nitrofuryl-2')-4-ethylcarbamoyl- S-amino-isoxazolehaving melting point 206 with decomposition.

EXAMPLE 17 The procedure described in Example 3 was carried out usingthe molecular equivalent of N-allylcyanoacetamide as starting materialinstead of the 1-cyanoacetylpyrrolidine, the reaction conditions beingotherwise essentially the same.

The product was 3-(5'-nitrofuryl-2)-4-allylcarbamoyl- S-amino-isoxazolehaving melting point approximately 220 EXAMPLE 18 By carrying out theprocedure described in Example 3 using the molecular equivalent of anyof the following amine reactants as starting material instead of the 1-cyanoacetylpyrrolidine there used:

N-cyanoacetylamino-n-propanol N'cyanoacetyl-fl-bromo-ethylamine 8 thereaction conditions being otherwise the same, the following products areobtained respectively: 3-(5'-nitrofuryl-Z) 4 'yhydroxypropylcarbamoyl-S-amino-isoxazole, 3-(5'-nitrofuryl-2') 4 Bbrornoethylcarbamoyl- S-amino-isoxazole.

EXAMPLE 19 By carrying out the procedure described in Example 5, usingthe molecular equivalent of methyl cyanoacetylcarbamate, isopropylcyanoacetylcarbamate or n-amyl cyanoacetylcarbamate, instead of theethyl cyanoacetylcarbamate there used, the reaction conditions beingotherwise essentially the same,3-(S-nitrofuryl-2)-4-(methoxycarbonylcarbamoyl -5-amino-isoxazole, 3- 5'-nitrofuryl-2 4- (isopropoxycarbonyl-carbamoyl) -5-amino-isoxazole or3-(5-nitrofuryl-2') 4 (n-amyloxycarbonylcarbamoyl)- 5-amino-isoxazole,is obtained respectively.

EXAMPLE 20 By carrying out the procedure described in Example 3 usingthe molecular equivalent of any of the following amines instead of thel-cyanoacetylpyrrolidine there used:

1-cyanoacetyl-ethylpiperidine 1-cyanoacetyl-thiomorpholine the reactionconditions being otherwise essentially the same, the following productsare obtained, respectively: 3-(5'-nitrofuryl-2) 4ethylpiperidinocarbonyl-S-aminoisoxazole, 3-(5'-nitrofuryl-2) 4thiomorpholinocarbonyl-5-amino-isoxazole.

EXAMPLE 21 The procedure described in Example 11 was carried out usingthe molecular equivalent of tertiary butyl cyanoacetate as startingmaterial instead of the methyl cyanoacetate, the reaction conditionsbeing otherwise essentially the same.

The product was3-(5-nitrofuryl-2')-4-(tertiarybutoxycarbonyl)-5-amino-isoxazole havingmelting point 171.

EXAMPLE 22 The procedure described in Example 11 was carried out usingthe molecular equivalent of fi-chloroethyl cyanoacetate as startingmaterial instead of the methyl cyanoacetate, the reaction conditionsbeing otherwise essentially the same.

The product was3-(5'-nitrofuryl-2')-4-(l3-chloroethoxycarbonyl)-5-amino-isoxazole,having melting point initially at 152 following by resetting withsubsequent melting at 158.

Similarly by using the molecular equivalent of any of the followingcyanoacetates instead of the fl-chloroethyl cyanoacetates:

fi-chloropropyl cyanoacetate -chloropropyl cyanoacetate B-bromoethylcyanoacetate n-propyl cyanoacetate isobutyl cyanoacetate secondary-butylcyanoacetate w-hydroxy-n-hexyl cyanoacetate fi-hydroxy-n-butylcyanoacetate fl-methoxy-ethyl cyanoacetate the following products areobtained, respectively:

3 5 '-nitrofuryl-2' -4- fi-chloropropoxy-carbonyl -5- aminoisoxazole,

3 5 '-nitrofuryl-2' -4- ('y-chloropropoxy-carbonyl) -5- amino-isoxazolehaving melting point 158,

3 5 '-nitrofuryl-2) -4- fi-bromoethoxy-carbonyl -5- amino-isoxazole,

3 5'-nitrofuryl-2 -4- n-propoXy-carbonyl -5-aminoisoxazole havingmelting point 186,

3 (5 -nitrofuryl-2 -4- isobutoxy-carb onyl -5-aminoisoxazole havingmelting point 3 (5 -nitrofuryl-2 -4- (secondary-butoXy-carbonyl -5-amino-isoxazole having melting point 126",

9 3- 5-nitrofuryl-2 -4- (w-hydroxy-n-hexyloxy-carbonylS-amino-isoxazole, 3- (5 '-nitrofuryl-2 -4-(fi-hydroxy-n-butoxy-carbonyl -5- amino-isoxazole, 3- (5 -nitrofuryl-2-4- (B-methoxy-ethoxy-carb onyl) -5 amino-isoxazole.

EXAMPLE 23 By carrying out the procedure described in Example 3 usingthe molecular equivalent of any of the following amine reactants asstarting material instead of the malononitrile there used:

N-cyanoacetyl-sec-octylamine N-cyanoacetyl-n-dodecylamineN-cyanoacetyl-cyclohexylamine N-cyanoacetyl-p-bromoethylamineN-cyanoacetyl-'y-methoxypropylamineN-cyanoacetyl-y-isopropoxypropylamine the reaction conditions beingotherwise the same, the following products are obtained respectively:

These compounds, their functional derivatives, or mixture of any two ormore thereof may be formulated in a conventional manner withpharmacologically acceptable solid carriers or liquid diluents.

We claim:

1. A compound of the formula:

OzNl ----R o A /IL NHz wherein R is -CN, -COOR or R2 CON in which R isalkyl of 1 to 6 carbon atoms which is unsubstituted or substituted byhydroxy, halo or alkoxy of from 1 to 4 carbon atoms; alkenyl of 3 or 4carbon atoms; or cycloalkyl of from 5 to 7 carbon atoms; and

R is hydrogen;

R is hydrogen; alkyl of from 1 to 12 carbon atoms which is unsubstitutedor substituted by hydroxy, halo or alkoxy of from 1 to 4 carbon atoms;alkenyl of 3 or 4 carbon atoms; alkoxycarbonyl on which the alkoxy grouphas from 1 to 5 carbon atoms; or carbamoyl; or

R and R taken together, together with the nitrogen atom to which theyare attached are pyrrolidino, piperidino, morpholino, thiomorpholino,piperazino or 4-lower i alkylpiperazino.

2. A compound according to claim 1 wherein R is 3. A compound accordingto claim 2 wherein R is alkyl of 1 to 5 carbon atoms.

6. A compound according to claim 5 wherein R is hydrogen and R is alkylof 1 to 5 carbon atoms which is unsubstituted or substituted by hydroxy.

7; A compound of the formula OzN-K wherein R is cyano, carboxamido orcarb(lower alkoxy).

8. A compound as defined in claim 1 which is 3-(5'-nitrofuryl-2)-4-cyano-5-amino-isoxazole.

9. A compound as defined in claim 1 which is 3-(5' nitrofuryl-2-4-carbamoyl-5-amino-isoxazole.

10. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z-4-pyrrolidinocarbonyl-S-amino-isoxazole.

11. A compound as defined in claim 1 which is 3-(5-nitrofuryl-Z')-'4-piperidinocarbonyl-5-amino-isoxazole.

12. A compound as defined in claim 1 which is 3-(5'-nitrofuryl-Z')-4-(ethoxycarbonyl-carbamoyl) 5 aminoisoxazole.

13. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z'-4-ethoXycarbonyl-S-amino-isoxazole.

14. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-2'-4-morpholinocarbonyl-S-amino-isoxazole.

15. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-2'-4-ureidocarbonyl-5-amino-isoxazole.

16. A compound as defined in claim 1 which is 3-(5-nitrofuryl-Z')-4-(B-hydroxyethyl-carbamoyl) 5 aminoisoxazole.

17. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-2'-4-methoxycarbonyl-S-amino-isoxazole.

18. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z'-4-isopropoxycarbonyl-S-amino-isoxazole.

19. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z'-allyloxycarbony1-S-amino-isoxazole.

20. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z) 4cyclohexyloxycarbonyl 5 aminoisoxazole.

21. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-2'-4-methylcarbamoyl-S-amino-isoxazole.

22. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z-4-ethylcarbamoyl-S-amino-isoxazole.

23. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z'-4-allylcarbamoyl-S-amino-isoxazole.

24. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-2') 4tertiarybutoxycarbonyl 5 aminoisoxazole.

25. A compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z) 4(fi-chloroethoxycarbonyl) 5 aminoisoxazole.

References Cited UNITED STATES PATENTS 3,321,474 5/1967 Kano et al260-247.5

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

